Transmissible spongiform encephalopathies (TSE) are a group of rare neurodegenerative diseases which include Creutzfeldt-Jakob disease (CJD) in humans, scrapie in sheep, bovine spongiform encephalopathy (BSE) and chronic wasting disease (CWD) in mule deer and elk. TSE infectivity can cross species barriers. The fact that BSE has infected humans in Great Britain and concerns that CWD may act similarly in the US underscores the importance of understanding TSE pathogenesis and developing effective anti-TSE therapeutics. The precise nature of the infectious agent of the TSE diseases is unknown. Susceptibility to infection can be influenced by amino acid homology between a normal host protein (PrP-sen) and the abnormal proteinase K-resistant form of this protein, PrP-res. Formation of PrP-res is closely associated with infectivity and PrP-res is widely considered to be the infectious agent in the TSE diseases. An understanding of how this protein is made is critical for our understanding of TSE pathogenesis and for devising therapeutic strategies to prevent its synthesis. My studies address many different aspects of the TSE diseases at both the molecular and pathogenic level. In particular, my laboratory focuses on: 1) identifying the earliest events which occur during TSE infection, 2) precisely defining the different cellular compartments where PrP-res formation occurs, 3) determining the molecular basis of TSE strains and, 4) development of effective therapeutic TSE agents. In 2009, we utilized a mouse tissue culture system previously developed in my laboratory to study the role of the PrP-sen glycophosphatidyl-inositol (GPI) membrane anchor in TSE infection. The cells were infected with mouse scrapie and the course of infection monitored. Our results suggest that, in scrapie-infected cells in vitro, the GPI anchored PrP-sen is essential for the establishment of a persistent TSE infection. We have also continued to develop both unique reagents and a new experimental model system that will allow us to follow the course of acute TSE infection in vivo.